PROJECT 2: SUMMARY Statins are among the most widely prescribed drugs in the western world, used to treat elevated cholesterol levels and reduce the risk of cardiovascular disease. While statins are highly effective and generally safe, adverse effects occur in a small proportion of users, which represents a large number of individuals due to statins' widespread use. In some individuals, statins adversely affect muscle, with symptoms ranging from mild pain to rhabdomyolysis. Recent studies have also shown a 9-12% increase in risk for type 2 diabetes among statin users. We hypothesize that many of the genetic variants and molecular mechanisms that influence statin-related myopathy and new-onset diabetes remain to be identified. In preliminary work, we have established that the mouse is a feasible model in which to identify genetic variation in statin-related muscle toxicity and dysglycemia, and it offers superior features for genetic and molecular analysis. In this Project, we will utilize a novel mouse genetics resource, the Hybrid Mouse Diversity Panel (HMDP), which consists of ~110 inbred mouse stains. We will use the HMDP to identify genes (Aim 1) and mechanisms (Aim 2) underlying statin-associated myotoxicity and diabetes. In Aim 3 we will perform in vivo studies in the mouse to validate selected genes identified in human studies in other projects within this Center. Innovative features of our approach include the ability to perform genetic association to high resolution in the HMDP, often to loci containing just a handful of genes. Additionally, our studies will include full HMDP sets of males and females, providing the opportunity to identify sex-specific statin effects. Our preliminary studies have identified effects of statins on protein kinase D signaling and autophagy in myocytes and beta cells, and we will elucidate these further at the physiological, cellular and molecular levels. These studies, together with the translation of human genetic variants to in vivo mouse models, will inform us about potential genetic and molecular markers that may be valuable for the evaluation of individual benefit versus risk of statin drug treatment.